Environmentally sensitive hotspots in the methylome of the early human embryo.

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Saffari, Ayden 
Kessler, Noah J 
Chandak, Gririraj R 
Fall, Caroline HD 

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental 'hotspots' providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.

DNA methylation, conception, early embryo, epidemiology, genetics, genomics, global health, human, metastable epiallele, nutrition, parent-of-origin effects, Child, CpG Islands, DNA Methylation, Embryo, Mammalian, Epigenesis, Genetic, Epigenome, Fertilization, Humans
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eLife Sciences Publications, Ltd
Medical Research Council (MC_U123292701, MC-A760-5QX00, MC_EX_MR/M01424X/1, MC_UU_00026/3, MR/N006208/1, MC_PC_MR/R020183/1, MC_U123292700, MC_UP_1005/1, MR/P012019/1, MR/M01424X/1, MR/T032863/1)
Bill and Melinda Gates Foundation (OPP1 066947)
Department of Biotechnology, Ministry of Science and Technology, India (BT/IN/DBT-MRC/DFID/24/GRC/2015-16)